Human immunodeficiency virus (HIV) is etiologically associated with the acquired immunodeficiency syndrome (AIDS). Promising new approaches being developed to control HIV infection and AIDS include gene therapy using retroviral vectors to deliver a protective gene or information. One objective of this project is to develop HIV, particularly HIV-2, based retroviral vectors. HIV has the obvious advantage of cell tropism and HIV-2 has the added advantage that it can infect stem cells. A series of HIV-2 based delivery vectors have been constructed, containing long terminal repeats (LTR) for regulated expression, gag sequences for packaging efficiency and the neo genes for cell selection. To test their functionality, they have been engineered to contain tat or antisense tat, transfected into lymphocytic cell lines and subjected to neo-selection. Cells transduced with vectors contain tat produced functional Tat protein and those transduced with anti sense tat will soon be challenged with virus infection. In an effort to map the HIV-2 packaging signal, it was discovered that the HIV-2 genome contains a negative regulatory element at a position thought to contain a packaging signal. Studies attempting to map the HIV-2 packaging signal are continuing. A novel regulatory element in the HIV-2 LTR was recently delineated. This element, located upstream of the enhancer-promoter region, functions in a cell-type dependent manner. These observations may be relevant to viral latency and virulence. It was found that the generation of mature transcripts of HIV- 2 involves a specific splicing within the LTR for some fraction of the transcripts. Since this splicing involves a region rich in regulatory elements, it is likely to have important consequences for viral latency and pathogenesis. It was discovered that HIV-2 provirus inhibits HIV-1 LTR expression as well as HIV-1 replication. This suggests that HIV-2 provirus may produce a transactivator which downmodulates HIV-1 gene expression. Such a factor may be therapeutically useful for controlling HIV-1 expression.